Despite the availability of effective therapy for more than 50 years, tuberculosis remains a leading cause of death and disease worldwide. Recently, the TB pandemic has been exacerbated by urban crowding, inadequate diagnostic and treatment infrastructure, increased host susceptibility due to HIV, and the emergence of drug resistance. The World Health Organization has proposed use of directly observed therapy, short course (DOTS) at the principal weapon to control TB globally. Despite the success of DOTS in developed countries, there is compelling evidence that DOTS alone may be insufficient to contain TB in developing countries. Alternative approaches to improve TB control have been mathematically modeled, but have not been validated in field trials. The propose of this multiproject ICIDR application is to evaluate innovative approaches to TB control in Rio de Janeiro in a series of interconnected studies at the community, patient and laboratory levels. The program is a collaboration between Johns Hopkins University, the University of Pittsburgh, the Department of Health of Rio de Janeiro and the Federal University of Rio de Janeiro. We propose three innovative research projects, supported by administrative and molecular diagnostic cores. Project 1 is a randomized trial of alternative strategies for implementing DOTS at the community level. We will randomized two communities to receive either DOTS alone or DOTS plus intervention evaluation and chemoprophylaxis in household contacts (DOTS+). The outcomes of the trial will be the incidence of TB and the extent and size of molecular clustering of TB after 4 years. Project 2 is a randomized trial of two short-course regimens to prevent TB in high-risk contacts of active cases identified in Project 1. Contacts will be randomly assigned to receive rifapentine and INH weekly for 12 weeks or rifampin/pyrazinamide twice weekly for 8 weeks. Contacts will be randomly assigned to receive rifapentine and INH weekly for 12 weeks or rifampin/pyrazinamide twice weekly for 8 weeks. We will enroll 650 patients in this Phase II trial, with endpoints of efficacy of the two regimens, safety, adherence and emergence of drug resistance. We will also compare DNA fingerprints in treatment failures to determine the extent of reinfection. Project 3 is a series of studies of novel diagnostic methods for M. tuberculosis diagnosis and detection of drug resistance. Following pilot studies at the University Hospital we will conduct field assessments of the most promising assays in the health posts from Project 1. An administrative core will provide logistical oversight, as well as scientific and technical support. A molecular diagnostics core laboratory will conduct DNA fingerprinting and develop and assess novel diagnostic assays. We have assembly an outstanding team of investigators collaborating in a unique field setting to develop improved and practical methods for TB control. We believe this project has exceptional potential to make important contributions too global TB control.